The invention relates to a pharmaceutical system aimed at increasing the bioavailability of orally administered drugs belonging to the following categories: (a) large molecular weight drugs, (b) drugs that lose their potency in the gastrointestinal (GI) tract as a result of enzymatic degradation.
In the following paragraphs protein drugs will be discussed as typical examples of drug molecules that are either large molecules or highly susceptible to enzyme degradation. However, additional non-proteinous drugs can be included in this group and they will be discussed later.
Medical use of protein drugs is constrained by three major drawbacks. The first is their short biological half-life which requires, in some cases, frequent administrations. The second is the rapid degradation which occurs in mucosal tissues that generally cover the body cavities. Lastly, most protein drugs are large molecules and therefore do not easily cross the intestinal epithelium. Therefore, the most common mode of protein drugs administration is the parenteral route. However, apart from the inconvenience to the patients, parenteral delivery systems are also more expensive in terms of production and drug administration. There is therefore a need for an effective non-parenteral mode of administration of protein drugs that will provide protection against biological degradation and/or enhance its transport across mucosal barriers. Although sophisticated non-parenteral pharmaceutical systems, such as intra-nasal systems, have been developed, oral administration is more favorable, having the major advantage of convenience for increased patient compliance. Sometimes oral administration of peptides offers physiological advantages, for example oral administration of insulin is superior to parenteral administration because, like the native hormone secreted by the pancreas, it also drains primarily into the portal vein to exert its initial effect on the liver. Some insulin will then find its way into the peripheral circulation via lymphatic channels [Goriya, Y., et al., Diabetologia 19:454-457 (1980)]. In contrast, injected insulin is drained entirely into the peripheral circulation and has access to all parts of the body. Notwithstanding these advantages, most protein drugs have not been orally delivered to date because of the lack of a simple and reliable drug delivery system that will be able to overcome the biological and physico-chemical constraints mentioned above.
An effective oral carrier for protein drugs should (a) shield its content against the luminal and brush border peptidases and (b) be capable of facilitating the uptake of the protein drugxe2x80x94usually a large molecular weight entityxe2x80x94across the gastrointestinal (GI) epithelium. Many studies have reported that protein drugs such as insulin, vasopressin, calcitonin, enkaphalins and thyrotropin-releasing hormone (TRH) were administered relatively successfully via the oral route [Lee, V. H. L., et al, Oral Route of Peptide and Protein Drug Delivery, in V. H. L. Lee (Ed.): Peptide and Protein Drug Delivery, Marcel Dekker, 1991 New York, pp 691-738]. An increase in the bioavailability of protein drugs after oral administration can be accomplished by the co-administration of either peptidases inhibitors, to help keep the protein drug as intact as possible at the site of absorption, or of protein absorption enhancers. Some works report the use of both absorption enhancers and peptidase inhibitors in the same formulation [e.g. Ziv, E., et al., Biochem. Pharmcol. 36:1035-1039 (1987)]. Some typical examples of oral administration of the protein drug insulin together with peptidase inhibitors or absorption enhancers are listed below.
Morishita et al. [Int. J. Pharm. 78:1-7 (1992)] found that after formulating insulin together with protease inhibitors such as trypsin inhibitor, chemostatin, Bowman-Birk inhibitor and aprotinin into Eudragit L-100(copyright) microspheres, the insulin was resistant to pepsin, trypsin and xcex1-chymotrypsin in vitro. However, in similar experiments performed in vivo by Laskowski and coworkers in which insulin was injected together with soybean trypsin inhibitor (SBTI) or, alternatively, without any inhibitor, a very small pharmacodynamic response was observed [Laskowski, M., Jr., et al., Science 127:1115-1116 (1958)]. Similar results were observed by Danforth and coworkers who also found that diisopropylfluorophosphate was an effective depressant of insulin digestion, while SBTI was not [Danforth, E., et al., Endocrinology 65:118-123 (1959)]. In contrast, it was found that the addition of SBTI solution boosted the pharmacological effect of insulin, namely reduction of blood glucose level, after its injection into the lumen of rat ileum [Kidron, M., et al., Life Sci. 31:2837-2841 (1982)]. Takahashi et al. used decanoic acid to enhance the absorption of the hydrophilic non-absorbable marker phenol sulfon phthalate. They found that the absorption correlated to the rate of disappearance of the decanoic acid from the intestine. The absorption onset was within few minutes. This indicates that there is a rationale to apply an absorption enhancer for improved functioning of the delivery system.
Table A and Table B hereunder itemize some examples of absorption enhancers and protease inhibitors reported in the literature.
van Hoogdalem E. J. et al., Pharmac. Ther. 44:407-443 (1989);
Muranishi S., Crit. Rev. Ther. Drug Carrier Sys., 7:1-34 (1990);
Geary, R. S. and Schlemeus, H. W., J. Contr. Release, 23:65-74 (1993);
Touitou, E. and Rubinstein A., Int. J. Pharm. 30:95-99 (1986);
Kraeling, M. E. K. and Ritschel, W. A., Meth. Find. Exp. Clin. Pharmacol. 14:199-209 (1992)].
Takahashi, K. et al., Pharm. Res. 11:388-392 (1994);
Takahashi, K. et al., Pharm. Res. 11:1401-1404 (1994);
Hochman, J. H. et al., J. Pharmacol. Ex. Ther. 269:813-822 (1994).
Absorption enhancement has been found to be very efficient in the improvement of the bioavailability of poorly soluble drugs especially in organs such as the nasal cavity and the rectum where prolongation of the drug delivery system""s residence time can be accomplished relatively easily [Hochman J. and Artursson P., J. Contr. Rel., 29:253-267 (1994)]. However, data on the enhancement of drug uptake in the GI tract are available primarily from in vitro studies. In such kind of studies the absorption modulator(s) is placed (or perfused in a constant rate) over unreal period of time. Some studies reported on prolonged pharmacological effect [Geary R. S. and Schlameus H. S., J. Contr. Release 23:65-74 (1976); Damge"", et al., Diabetes 31:246-251 (1988)]. This effect was achieved either when relatively high amounts of absorption enhancers were used, or when microparticles and bioadhesion techniques were employed. Under normal conditions the motility of the small intestine pushes a solid dosage form so that it stays very briefly in the vicinity of the absorbing mucosa. Therefore it is reasonable to assume that a controlled release technology is required to xe2x80x9cseedxe2x80x9d constant amounts of enhancer(s) along the digestive tube. Yet, the absorption modulator should be released in a rate similar to the release rate of the protein drug. The simplest way to achieve such a synchronization would be with a large, erodible dosage form. It will be difficult for a particulate dosage form to accomplish such synchronization because the spreading effect caused by gastric emptying under fasted conditions. Table C hereunder summarizes some techniques for the oral delivery of peptide drugs based on ordinary controlled release concepts.
When a protein drug is formulated together with an absorption enhancer and/or peptidase inhibitor into an oral dosage form, the rate of supply of the formulation functional ingredients into the aqueous milieu of the GI tract becomes crucial. It is important for the release rates to be slow and controllable [i.e. the release rates of the protein drug, the peptidase inhibitor(s) and/or the absorption enhancer(s) must all be slow and synchronized] for the following reasons: (a) To improve its absorption the protein drug should be continuously accompanied by its xe2x80x9cguardxe2x80x9d molecules, i.e. the peptidase inhibitor or the absorption enhancer, or both of them, until the drug""s absorption has been completed; (b) A synchronized slow release from the delivery system will ascertain a prolonged drug supply to the body which will result in a desired and sufficient pharmacodynamic response, hereby overcoming the limitation of the short biological half life of the protein drug; (c) An uncontrollable, immediate release of the protein drug together with the protease inhibitor and/or the absorption enhancer (from dosage forms such as enteric coated capsules, or microcapsules or microparticulate delivery systems) could cause an unrestrained dilution of the drug with the fluids of the alimentary canal. This might reduce the concentration of the drug into values below those required to maintain effective concentration gradients across the intestinal epithelium; (d) Since various formulation components (the protein drug, the absorption enhancer and the protease inhibitor) differ from each other by their physico-chemical properties (solubility, dissolution constants, mode of dissolution, and partition coefficients) difficulties are likely to arise in the design of an oral delivery system of protein drugs, especially the systems that release their drug content in a burst manner (enteric coated capsules), or rely on diffusion throughout a membrane (microcapsules, coated tablets).
There are some non-proteinous drugs that suffer from similar constraints upon oral administration. It is well recognized now that the Phase I metabolic enzyme cytochrome P-450 is active in the intestinal brush border. In the rat the villus tip cells contain higher amounts of this enzyme than the crypt cells, and the enzyme content in the small intestine is larger than the colon [Hoensch H. et al., Biochem. Biophys. Res. Commun. 65:399-406 (1975)]. A longitudinal gradient of Cyto-chrome P-450 exists also in humans [Peters W. H. M. et al., Gastro-enterology, 96:783-789 (1989)]. As a result, drugs such as benzphetamin [Oshinski R. J. and Strobel H. W., Int. J. Biochem. 19:575-588 (1987)) and cyclosporine [Benet L. Z., et al., Proceedings of the 7th International Symposium on Recent Advances in Drug Delivery Systems, Salt Lake City, Utah, pp. 11-14 (1995)] are susceptible to first-pass brush border metabolism and their bioavailability is decreased significantly. Appropriate cytochrome P-450 inhibitors such as metyrapone, n-octylamine or propafenone, if formulated in erodible delivery systems as described above, may be able to provide reasonable protection to such drugs after oral ingestion. It is noteworthy that although being an oligopeptide, cyclosporine is not metabolized by the gut peptidases but rather by cytochrome P450-dependent monooxygenase [Fahr A., Clin. Pharmacokin. 24:472-495 (1993)].
An example for a drug that undergoes brush border metabolism after oral administration and could benefit from being incorporated into an erodible delivery system with suitable enzyme inhibitor is morphine which is degraded by mucosal glucuronyl transferase. Its bioavailability after oral administration is much lower than after parenteral administration [Osborne R. et al., Clin. Pharmacol. Ther. 47:12-19 (1990)].
A rational design for an oral delivery system of a protein drug would therefore be one in which the synchronized release is accomplished by an erodible matrix. In such a dosage form the release of the protein drug and the functional adjuvants do not depend upon intrinsic diffusion processes but rather are the result of the rate of the matrix erosion. By stripping off the erodible matrix layers in a well controlled manner predetermined amounts of the drug and its xe2x80x9cguardsxe2x80x9d, the protease inhibitor(s) and the absorption enhancer(s), will be placed together along the desired segment of the GI tract so that constant and optimal drug blood concentrations are achieved. The successful functioning of the matrix tablets depends upon the ability to xe2x80x9cfine tunexe2x80x9d its erosion rate. Superior performance can be achieved if part of the matrix tablet components are able, by virtue of their own properties, to serve as peptidase inhibitors. Typical examples of these kinds of polymers are the loosely crosslinked acrylic polymers Carbopol and polycarbophil (PCP). It has been shown that they provide protection to some peptide drugs [Borchard G. et al. Proceedings of the 7th International Symposium on Recent Advances in Drug Delivery Systems, Salt Lake City, Utah, 1995, pp. 7-10, Bai J. P-F., et al., ibid., pp. 153-154]. A major drawback of these polymers for the purpose of the suggested technology is their extremely high swelling properties which cause them to disperse in aqueous solutions within 30 minutes. Therefore a supportive, hydrophobic polymer such Eudragit(copyright) RL must be incorporated into the matrix delivery system (e.g. by forming a polymer blend) in order to achieve a firm hydrogel which will erode (but not create a diffusional barrier) and to establish a control over the erosion rate of the dosage form. Hydrogel forming materials such as the above mentioned polycarbophil or the polycarbophil blend with Eudragit(copyright) PL must be able to swell in the GI tract and at the same time erode. If they only swell , they will create a diffusional barrier (a conventional sustained release formulation) that will risk the synchronized release. For the purpose of erodible matrix hydrogels additional materials can be used. Some good candidates for this are saccharidic hydrogels such as natural gums and their salts, e.g. alginic acid and its calcium saltxe2x80x94calcium alginate, or pectin and its calcium salt calcium pectinate. If formulated properly these polysaccharides form hydrogels that exchange ions with the GI physiological fluids. As a result they lose their mechanical strength and erode while swelling in a controllable manner.
The present invention relates to a controlled release drug delivery system comprising a drug which is susceptible to enzymatic degradation by enzymes present in the intestinal tract; and a polymeric matrix which undergoes erosion in the gastrointestinal tract comprising a hydrogel-forming polymer selected from the group consisting of (a) polymers which are themselves capable of enhancing absorption of said drug across the intestinal mucosal tissues and of inhibiting degradation of said drug by intestinal enzymes; and (b) polymers which are not themselves capable of enhancing absorption of said drug across the intestinal mucosal tissues and of inhibiting degradation of said drug by intestinal enzymes; wherein when the matrix comprises a polymer belonging to group (b) the delivery system further comprises an agent which enhances absorption of said drug across the intestinal mucosal tissues and/or an agent which inhibits degradation of said drug by intestinal enzymes and when the matrix comprises a polymer belonging to group (a) the delivery system optionally further comprises an agent which enhances absorption of said drug across the intestinal mucosal tissues and/or an agent which inhibits degradation of said drug by intestinal enzymes.
The drug delivery system of the invention further provides a method for orally administering a drug which is susceptible to degradation by enzymes present in the intestine, or mixture of such drugs, to a patient in need of such drug.
The delivery system of the invention provides for the controlled release of not only the drug, but also of the inhibitor of the drug-degrading enzyme and/or the drug absorption enhancer. This synchronized release of the enzyme inhibitor and/or the absorption enhancer furnishes a constant protection against enzymatic degradation of the drug, which is also released from the hydrogel formed by contact with the physiological fluids in a sustained manner, upon the erosion thereof.
The invention also relates to a method of preparing the pharmaceutical delivery system according to the invention.